Summary ? Overall: T lymphocyte (T cell) responses against tumor antigens are key to cancer immunotherapy, and this proposal is focused on enhancing T cell mediated anti-cancer immunity using biomaterials. Defects in T cell number, differentiation, activation and anti-cancer activity can compromise anti-cancer immunity. We envision biomaterials that act at various stages of T cell differentiation and activation to enhance anti-cancer immunity in a number of settings. This i3 Center will advance efficacious biomaterial-based immunotherapies through marrying the expertise in bioengineering from accomplished investigators at the Wyss Institute for Biologically Inspired Engineering with the expertise in cancer immunology, stem cell biology, and clinical oncology from accomplished basic and translational scientists at the Dana-Farber Cancer Institute and Massachusetts General Hospital. Our groups have made major contributions to the development of checkpoint blockade therapy, neoantigen vaccines, cellular therapies, and therapeutic biomaterials in the past, and here will take a material- based approach to address a number of related, fundamental questions in immunoengineering. The Specific Aims of the i3 Center are: (1) To develop artificial antigen presenting cells that closely mimic normal T cell activation to selectively expand large numbers of highly functional polyclonal antigen-specific CD8 T cells, and explore if adoptive transfer of polyclonal T cells will provide tumor control. (2) Determine if co-delivery of neoantigens and adjuvants with precise nanoscale distribution and stoichiometric loading, using DNA origami, can provide a powerful platform to boost the development of cytotoxic T lymphocyte anti-cancer responses, and (3) Create biomaterials which recreate key features of the normal hematopoietic stem cell niche, and utilize to enable rapid reconstitution of T cells in settings where there are deficiencies in T cell number and repertoire, in order to enhance generation of T cell-mediated anti-cancer immunity. The leadership and organizational structure of the i3 Center, which includes a Biostatistics Core, reflect the close collaboration among the participating disciplines and institutions, and will promote the effective execution of the proposed work and its future translation to clinical testing. The synergistic set of activities in the i3 not only address specific stages where immune control can fail, but the lessons learned and technologies developed in each project strongly impact the others. The Center is expected to yield major scientific and translational advances in cancer immunotherapy.